Previous studies have demonstrated the coexistence of a cholecystokinin (CCK)-like peptide in a subpopulation of mesencephalic dopamine (DA)-containing neurons in the brain of rat and man. These CCK-DA cells were present predominantly in the ventral tegmental area (VTA or A10). The A10 DA cells project primarily to limbic and cortical regions of the brain and have a postulated role in the pathophysiology of schizophrenia and in the therapeutic actions of antipsychotic drugs. Recently, Chang et al., reported that following chronic treatment with the antipsychotic drug haloperidol, there was an increase in brain 125I-CCK-33 binding sites. Interestingly, in guinea pigs, the increased CCK binding was observed in the mesolimbic regions and frontal cortex, but not in neostriatum. These findings indicate that (1) CCK is intimately interacting with the DA system and (2) CCK may play a role in the antipsychotic action of haloperidol. Indeed, in pilot clinical trials, CCK appears to have antipsychotic properties. The purpose of the present project is to elucidate the functional significance of the coexistence of CCK and DA at the cellular level. Since it has been established that CCK-DA cells in A10 project to the caudal and medial part of the nucleus accumbens (NAc), we propose to study the effects of CCK and DA in the NAc. Specifically, by using combinations of single unit recording, microiontophoretic (or micropressure) administration of drugs, electrical stimulation, lesions, retrograde tracing and immunocytochemical staining, push-pull cannula perfusion and biochemical manipulations, we propose to study the influences of CCK, DA and putative transmitters on the physiological activity of identified neurons in the NAc. In addition, physiological and pharmacological effects of CCK will be characterized and interactions among CCK, DA and other transmitters will be determined. These studies are essential for an understanding of the functional significance of CCK-DA coexistence in the mesolimbic DA system. It is hoped that this knowledge ultimately will lead to a greater understanding of the possible neuronal mechanisms underlying psychosis, as well as to the development of antipsychotic agents with optimal therapeutic properties and minimal neurological side effects.